Impaired feedforward inhibition of the thalamocortical projection in epileptic Ca2+ channel mutant mice, tottering

Sachie Sasaki, Kadrul Huda, Tsuyoshi Inoue, Mariko Miyata, Keiji Imoto

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The tottering (tg) mice have a mutation in the CaV2.1 (P/Q-type) voltage-dependent Ca2+ channel α12.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at ∼3 weeks of age and persists throughout life. Similarities in EEG and sensitivity to antiepileptic drugs suggest that tg mice are a good model for human absence epilepsy. Although imbalance between excitatory and inhibitory activity in the thalamocortical network is thought to contribute to the pathogenesis of absence epilepsy, the effect of the mutation on thalamocortical synaptic responses remains unknown. Here we showed imbalanced impairment of inhibitory synaptic responses in tg mice using brain slice preparations. Somatosensory thalamocortical projection makes not only monosynaptic glutamatergic connections but also disynaptic GABAergic connections, which mediate feedforward inhibition, onto layer IV neurons. In tg mice, IPSC amplitudes recorded from layer IV pyramidal cells of the somatosensory cortex in response to thalamic stimulation became disproportionately reduced compared with EPSC amplitudes at later developmental stages (postnatal days 21-30). Similar results were obtained by local stimulation of layer IV pyramidal neurons. However, IPSC reduction was not seen in layer V pyramidal neurons of epileptic tg mice or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (postnatal days 14-16). These results showed that the feedforward inhibition from the thalamus to layer IV neurons of the somatosensory cortex was severely impaired in tg mice and that the impairment of the inhibitory synaptic transmission was correlated to the onset of absence epilepsy.

Original languageEnglish
Pages (from-to)3056-3065
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number11
DOIs
Publication statusPublished - Mar 15 2006
Externally publishedYes

Keywords

  • Absence seizure
  • Ca channel
  • Feedforward inhibition
  • Mutant mice
  • Synaptic transmission
  • Thalamocortical projection

ASJC Scopus subject areas

  • Neuroscience(all)

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